The exquisite sensitivity and discrimination capabilities of mammalian olfaction arise from a combination of novel genetic regulatory mechanisms, cellular specializations, and the overall anatomy and architecture of the olfactory system. One of the key aspects of genetic control is the selective expression of one allele of a single olfactory receptor (OR) gene in each sensory neuron. Past research in this area has demonstrated this one-receptor one-neuron principle and revealed an important role for the olfactory receptor protein for feedback that establishes and maintains this relationship. A molecular understanding of processes underlying this regulation has been hampered by the complexity and effort required to examine these process in genetically modified animals. Experiments in transgenic mice by several investigators, including our own, have suggested an additional critical role for the receptor coding sequence in determining the transcription state of the receptor. In this grant we will use molecular and genetic approaches to elucidate mechanisms responsible for the remarkable regulation of OR expression. We will test the hypothesis that nucleic acid sequences within the protein coding regions of ORs control functional expression at the genomic, transcriptional or translational level and that this activityis important for proper OR expression. In specific aim 1, we utilize a cell culture model to investigate and understand mechanistically one aspect of OR expression. In parallel, we propose to determine the sequences within the OR coding sequence that are responsible for this unusual regulatory process. In specific aim 2, we will utilize genetically modified mice to examine the consequences of altering this regulation in vivo. Together, these experiments may reveal new mechanisms of gene regulation. The proposed research will incorporate novel expression systems and a broad array of molecular methods to systematically study a regulatory process that is likely to be shared by other biological systems Elucidating these mechanisms may provide additional insight in genes that play critical roles in human health and disease.